Pharmacogenomic Effects of β-Blocker Use on Femoral Neck Bone Mineral Density

Abstract

Context Recent studies have shown that β-blocker (BB) users have a decreased risk of fracture and higher bone mineral density (BMD) compared to non-users, likely due to the suppression of adrenergic signaling in osteoblasts, leading to increased BMD. There is also variability in the effect size of BB use on BMD in humans, which may be due to pharmacogenomic effects. Objective To investigate potential single nucleotide polymorphisms (SNPs) associated with the effect of BB use on femoral neck BMD, we performed a cross-sectional analysis using clinical data, dual-energy X-ray absorptiometry, and genetic data from the Framingham Heart Study’s (FHS) Offspring Cohort. We then sought to validate our top four genetic findings using data from the Rotterdam Study, the BPROOF Study, the MOFS, and the Hertfordshire Cohort Study. Design We used sex-stratified linear mixed models to determine SNPs that had a significant interaction effect with BB use on femoral neck (FN) BMD across 11 gene regions. We also evaluated the association of our top single nucleotide polymorphisms (SNPs) from the FHS with microRNA (miRNA) expression in blood and identified potential miRNA-mediated mechanisms by which these SNPs may impact FN BMD. Results One polymorphism (rs11124190 in HDAC4) was validated in females using data from the Rotterdam Study, while another (rs12414657 in ADRB1) was validated in females using data from the MOFS. We performed an exploratory meta-analysis of all 5 studies for these polymorphisms, which further validated our findings. Conclusions This analysis provides a starting point for investigating the pharmacogenomic effects of BB use on BMD measures.